Whether the initial dose of the first human trial is reasonable or not is directly related to the success or failure of the trial. When determining the initial dose, it is necessary to comprehensively consider the existing animal efficacy, toxicity and pharmacokinetic research data, and it is necessary to avoid excessive initial doses. It can lead to serious adverse reactions to ensure the safety of the subjects, and it is necessary to consider reaching the test goal quickly without increasing the number of subjects.
This article introduces in detail according to the pre-clinical in vitro or in vivo toxicity and pharmacological activity level exposure, the corresponding human pharmacokinetic parameters are estimated, and the drug action and target characteristics are comprehensively considered to obtain the expected human pharmacodynamics or toxic dose, and compare and determine A reasonable initial dose method for the first clinical trial is to effectively reduce the risk of the first human trial and increase the success rate of the trial.
The First Human Trial (FIH) is an important turning point and milestone in the development of innovative drugs. Due to the existence and uncertainty of species differences, there may be a great safety risk when exploring the human body tolerable dose range based on preclinical pharmacology and toxicology research data.
In 2006, when the first human trial of the monoclonal antibody drug TGN1412 was conducted in the United Kingdom, 6 healthy volunteers developed headache, myalgia, dyspnea, head and neck swelling and other symptoms about 1 hour after injection of the initial dose of the drug, and then developed lungs. Infiltration, lung injury, kidney injury, and diffuse intravascular coagulation eventually resulted in the removal of all toes and part of the fingers of a volunteer.
After a lapse of 10 years, a similar tragedy occurred again. In the BIA 10-2474 multiple-dose human tolerance test conducted in France in 2016, a healthy volunteer died after 5 consecutive oral administration of 50 mg of the test drug for 7 days, and another 5 One subject had symptoms of brain injury.
These two serious first human trial events once again show that the risk of the first human trial is greater. The scientificity of the test drug dosage and dosing regimen is very important. Too high a dose may cause serious or even irreversible safety problems.
This article aims to introduce the method of scientifically estimating the initial dose of the first human trial based on pharmacological and toxicological data and pharmacokinetic (PK) research results obtained preclinically.
In 2005, the U.S. Food and Drug Administration (FDA) issued the guidelines for the estimation of the initial dose for the first human trial, which detailed the idea, strategy and method of using the NOAEL value to calculate the maximum recommended starting dose (MRSD) for the first human trial. The calculation of the initial dose recommended by this guideline is mainly based on the results of long-term animal toxicity studies that have been obtained. The NOAEL is determined based on the animal toxicology experiment data. By comparing and selecting the corresponding data of the most sensitive animal, the body surface area normalization method is used to directly convert the corresponding data. Human equivalent dose (HED).
Comprehensive consideration of animal and human pharmacological activity and PK characteristics, animal model limitations and receptor characteristics and other factors, adjust and select an appropriate safety factor to determine the initial dose of FIH.
This method is easy to calculate, but if there are obvious species differences in the PK characteristics, exposure-response relationship, or binding characteristics of the drug, it may lead to large deviations in the human equivalent dose obtained by direct conversion.
After the TGN1412 event, the European Medicines Evaluation Agency (EMEA) promulgated in 2007 guidelines for the calculation of the initial dose of high-risk products in the first human trial. The MABEL method is recommended, emphasizing the comprehensive consideration of in vitro drug concentration-effect relationships and in vivo animal doses. -Exposure-response relationship, using key PK parameters obtained in preclinical animal experiments, such as clearance rate (CL), apparent volume of distribution (Vd), etc., to predict human PK parameters, based on expected pharmacological activity or toxic exposure, Calculate the corresponding human biologically active dose:
Human dose = animal body AUC × predicted human body CL, or human body dose = animal body homeostasis
Blood concentration (CSS) × predicted human body Vd.
This method can also combine the mode of action of the drug, the characteristics of the target point, the shape of the dose-response curve, etc., to determine the MABEL value through safety factor correction.
For certain types of drugs or biological products (such as vasodilators, anticoagulants, monoclonal antibodies or growth factors), adverse drug reactions may result from excessive pharmacological effects. At this time, the expected pharmacologically active dose (PAD) It may be a more sensitive indicator of potential toxicity than NOAEL, so MRSD may need to be reduced.
After the BIA event, EMEA issued guidelines again in November 2016 to identify and evaluate the many risks in the first human trials and early clinical trials of new drugs. It is recommended that NOAEL and MABEL be used to calculate the starting dose, and the lowest dose is selected as the FIH finalizes the initial dose, and emphasizes the need to comprehensively consider the results of preclinical pharmacodynamics to estimate the human PAD or expected therapeutic dose range (ATD), as well as drug target binding and receptor occupancy (RO).
For drugs with a clear target, the receptor affinity is closely related to the plasma free drug concentration. In vitro experiments can be used to obtain the drug dose and receptor occupancy rate curve, and then based on the results of the animal PK experiment to determine what is needed to achieve the expected receptor occupancy rate The concentration of the drug in the plasma (or in the tissue) is calculated, and the drug dose that should be given to reach this concentration is calculated, and then converted into the corresponding human equivalent dose according to the human and animal dose conversion coefficient.
Under normal circumstances, for receptor agonists, the receptor occupancy rate should be less than 10% as the initial dose in the first human trial, while for receptor antagonists, the receptor occupancy rate should be 10% as the initial dose.
The scientific calculation of human PK parameters from preclinical animal PK parameters is an important basis for accurate and reasonable calculation of human doses. There are many calculation methods to choose from. According to the PK characteristics of the drug being studied, one or more methods can be selected for calculation.
The allometric growth model calculation algorithm is currently the most widely used method to predict human PK parameters. It is assumed that the elimination process of the drug in the body is linear elimination. Taking the clearance rate CL as an example, different species CL and body weight (W) exist The following relationship.
CL = aWb
Based on the CL values of at least three different species of animals obtained before the clinic, a regression equation is established to obtain the values of constants a and b, and the total clearance rate of the human body is calculated accordingly. When using this method, the exponential rule should be followed, that is, when the exponent b is between 0.55 and 0.70, the simple allometric mode can be used;
When the index b is between 0.70 and 0.99, the maximum life value (MLP) should be substituted for the weight, and the above method should be used to predict the human PK parameters, or the following formula can be used to calculate.
When the index b>1.0, brain weight (BrW) can be used instead of body weight, and the above method can be used to predict human PK parameters, or the following formula can be used to calculate.
The same method can be used to predict the Vd value of the human body. In some special cases, pre-clinical research may only obtain PK data of one animal or when the researcher thinks a certain animal is the most suitable species, the fixed index method can be used, that is, human CL = animal CL × (human weight ÷ animal weight )0.75.
Similarly, when the preclinical research only obtains the PK data of two species of animals, the PK parameters can be calculated according to the corresponding empirical formula, which will not be repeated here.
The physical and chemical properties of the drug itself, tissue affinity, permeability, liver and kidney clearance rate, plasma protein binding rate, etc., as well as the body’s own physiological characteristics can affect the PK process of the drug in vivo.
When the factors involved in the drug PK process are particularly complicated, simple extrapolation can be used to predict the human drug-time curve from the animal drug concentration-time curve, and then gradually increase the corresponding variables, establish and optimize the PK model, and finally obtain a suitable model and corresponding human body PK parameter.
Physiological pharmacokinetic model (PBPK) can be followed by adding physical and chemical characteristic parameters of the drug (such as fat solubility, tissue affinity, etc.), species-specific physiological characteristic parameters (such as tissue organ weight, tissue blood flow, etc.), drug free fraction, and describing drug The kinetic parameters of the biochemical treatment process [such as the maximum reaction rate (Vmax), Michaelis constant (Km), etc.], tissue-specific metabolic enzymes and transporter gene expression profiles, are gradually optimized, and the final model can be used outside of species Push and predict the PK of different groups of people.
Among them, the in vitro characteristic parameters of drug tissue affinity, fat solubility, enzyme metabolism kinetics, etc. can be determined by in vitro experiments. The software usually provides physiological parameters such as the organ volume and surface area of the human body or common experimental animals, and can also be obtained from literature. Tissue or organ blood Flow rate is closely related to the metabolism and distribution of drugs in the body. It should be noted that rodents often use large venous blood vessels, while humans often use peripheral venous blood vessels. Full consideration should be given to setting different parameters when fitting the drug-time curve.
Take the caffeine PBPK fitting process as an example. As shown in Figure 1, the initial human PK characteristic curve (line 1) can be obtained by simple extrapolation from the caffeine mouse drug-time curve. After adding species-specific physiological data to the model , The distribution phase characteristics of the drug have been significantly improved (line 2), and on this basis, the human cytochrome P450 1A2 (CYP1A2) enzyme activity and the predicted tissue drug concentration and other pharmacokinetic parameters (line 3) are increased, and finally human The difference between the free drug fraction and the mouse free drug fraction, that is, the plasma protein binding rate, and other factors are re-fitted to obtain a final model (line 4) that is very close to the measured value (dot).
In addition, accurate estimation of PAD and ATD values based on preclinical PK/PD or exposure effect research results can reduce unnecessary human exposure and improve the efficiency of the first human test, which will not be repeated here.
When the main metabolic mechanism of the drug is liver metabolism, in vitro liver microsomes or isolated hepatocyte tests can be used to obtain the liver metabolism rate. It is assumed that the drug-metabolizing enzymes are uniformly distributed in the liver, and the distribution of drugs in the liver depends on liver perfusion. There is a diffusion barrier, and only free drugs can cross the membrane and occupy the active sites of enzyme metabolism. When the drug concentration is far below Km, the liver clearance rate CLint can be calculated according to the following formula.
Among them, Vmax is the maximum reaction rate, Km is the Michaelis constant, and f u is the free fraction of the drug in liver microsomes or liver cells. The human liver clearance rate can be calculated as follows:
Where Qh is the hepatic blood flow.
When CYP450 enzyme and glucuronidase are both involved in drug metabolism, the above formula is transformed into:
Calculate the total clearance rate of human liver by the sum of the two.
On the basis of the traditional VIVIE method, factors such as protein intake, drug dissociation, and pH value can be further considered to further optimize the model to calculate the drug clearance rate in the human liver. In addition, drugs that are mainly eliminated through the kidneys in their original form can also be used to calculate the human renal clearance rate through in vitro research data using similar methods.
In the past, based on the results of pre-clinical animal safety trials or the clinical therapeutic dose of similar drugs, such as the modified Blach Well method, the modified Fibonacci method or the Dollary method, there was a lack of scientific estimation of animal species differences. When the dose is much higher than the expected clinically effective dose, it may cause serious adverse drug reactions, so that the original potential effective drug cannot be continued to be developed; if the calculated starting dose is too low, it may cause too much Subjects are exposed to invalid doses, the research efficiency is reduced, and the research and development cycle is prolonged.
The core of the NOAEL or MABEL method is to fully consider the characteristics of the drug itself, the biologically active dose and the exposure, and calculate the corresponding human exposure based on the PK characteristics of the toxicity and pharmacologically active effect levels obtained in preclinical, combined with the target of the drug. Binding or receptor occupancy and other characteristics are used to obtain the expected human biologically active dose level, from which the FIH starting dose is estimated. Therefore, when designing the first human trial dose of an innovative drug, the results of preclinical research should be fully evaluated and a variety of methods should be used Calculate and compare to determine a reasonable starting dose for the first clinical trial, reduce risk, and increase the success rate of the trial.
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